DESCRIPTION (Applicant's Abstract): During the first 2 years of this project, the investigators have made a number of observations which support the hypothesis that substance P (SP) plays an important role in regulating mononuclear phagocyte function and affects HIV infection in vitro. They have demonstrated that human monocytes and lymphocytes express SP mRNA transcripts, including a novel isoform, and secrete SP protein. SP mRNA and protein are altered by HIV infection of these cells in vitro. The investigators propose to continue and extend the studies on the molecular mechanism(s) of SP modulation of HIV infection in human monocyte/macrophages (M/M) including brain microglia. They will study the mechanisms of interaction between SP and HIV, including the effects on NFkappaB binding to HIV promoter LTR, effects on HIV cycle replication, and effects on chemokine levels and chemokine receptor expression. The overarching hypothesis is that SP is affected by life stress, anxiety, and/or depression in HIV-infected patients and may be associated with progression of HIV infection, particularly CNS infection, by affecting immune cell functions. Circulating SP levels may increase as a result of HIV infection of M/M and/or the presence of acute or chronic life stress, anxiety and/or depression. Using peripheral blood samples from two adult cohorts of HIV+ and HIV- men and women, they will test the hypotheses that SP is up-regulated by HIV infection in vivo, SP is further up-regulated by degree of life stress, anxiety and/or depression; and SP is a risk predictor for cognitive changes and/or CNS manifestations of HIV infection. Using PBMS, the investigators will relate SP protein and mRNA levels in cells derived from these cohorts to measures of psychiatric, neurologic, endocrine, immunologic and virologic status. These studies will provide new information about the biological link between the CNS and the immune system and may delineate a new marker that can be used to detect risk of progression in patients with HIV and/or life stress and depression.